The mammalian immune system is comprised of a complex array of molecular and cellular mediators that recognize and react to microbial antigens. Cell-mediated responses are critical for maintaining immunocompetence. Cell-mediated immune reactions are also thought to be responsible for undesirable responses such as those associated with allergy and certain autoimmune diseases.
T lymphocytes, or T cells, orchestrate cell-mediated immune responses. Antigens derived from polypeptides are presented to T-cells through a group of molecules known as MHC (major histocompatibility complex) molecules. MHC molecules are expressed on the surface of cells in association with small peptide ligands. A receptor on T cells (T cell receptor, or TCR) binds to MHC/peptide complexes on the surface of cells. In general, antigens presented by MHC class I molecules are recognized by CD8+ T-cells, while antigens presented by MHC class II molecules are recognized by CD4+ T-cells.
Antigen presentation to T cells also occurs through a distinct family of antigen presenting molecules, CD1 molecules. These proteins are displayed on antigen-presenting cells which include Langerhans cells, activated B-cells, dendritic cells in lymph nodes, activated blood monocytes, etc. Although there is a structural resemblance to MHC molecules, CD1 molecules differ from MHC molecules in a variety of ways. For instance, CD1 genes are apparently non-polymorphic, while human MHC genes are highly polymorphic, and, unlike MHC molecules, CD1 molecules present non-peptide antigens.
CD1 molecules are a class of antigen presenting molecules that bind lipid antigens, forming CD1-lipid complexes that activate T cells. CD1 proteins are structurally similar to the major histocompatibility complex class (MHC) I molecules, but do not vary substantially in structure within a population, as MHC molecules do. In humans, there are five CD1 proteins, CD1a, CD1b, CD1c, CD1d and CD1e. The CD1d protein has been previously shown to present α-galactosyl ceramide (αGalCer), α-glucosyl ceramide (αGluCer), phosphatidylinositol and glycosylphosphatidylinositol (GPI) to T cells (Kawano, Cui, Koezuka et al. 1997; Schofield, McConville, Hansen et al. 1999; Gumperz, Roy, Makowska et al. 2000). Thus, antigens known to be presented by CD1d are amphipathic glycolipids with two alkyl chains.
CD1-restricted immune responses have been implicated in responses to microbial antigens, and also in the regulation of autoimmune responses. In mice, CD1d-restricted T cells have been shown to mediate tumor rejection (Nakagawa, Motoki, Nakamura et al. 1998; Toura, Kawano, Akutsu, Nakayama, Ochiai, Taniguchi 1999), delay the onset of juvenile diabetes (Sharif, Arreaza, Zucker et al. 2001; Hong, Wilson, Serizawa et al. 2001), and mediate protection from infection by viruses and bacteria (Baron, Gardiner, Nishimura, Shinkai, Locksley, Ganem 2002; Nieuwenhuis, Matsumoto, Exley et al. 2002). αGalCer antigens are in phase I trials of humans with juvenile diabetes and metastatic cancers (Giaccone, Punt, Ando et al. 2002).